TMD (Temporomandibular joint disorders) affect 5-10% of the population in this country, with severe TMD requiring surgical repair. The cause for TMD is often hard to determine, and the pathophysiology underlying this affliction remains unclear, as the mandibular condylar cartilage (MCC) differs considerably in its development and structure from both a growth plate or an articular cartilage. However, the regulation of TMJ development and growth has been under-studied. Chondrogenesis in the TMJ or limbs has been considered a linked but separate process from osteogenesis during endochondral bone formation. How can the inherited message be transmitted from chondrocytes, which supposedly undergo cell death before bone formation, to the cells that form bone? The answer to this question may lie in recent studies indicating that a direct transformation of chondrocytes to osteoblasts occurs. Yet, the following key questions remain: how is this cell transformation linked to bone growth and remodeling? What is the underlying molecular mechanism? Which genes are required for cell transformation? We propose that chondrogenesis and osteogenesis are one continuous process in which chondrocyte-derived bone cells (CBC) define the overall pattern of MCC-ramus and contribute to bone remodeling via Bmpr1a (BMP receptor 1a, a key receptor for BMP2 and BMP4) and ?-catenin. This hypothesis is based on: 1) Published data from our lab and others demonstrating that direct cell transformation occurs in MCC and limbs; 2) Deleting Bmpr1a or ?-catenin in chondrocytes leads to drastic changes in the condyle and limbs during growth and bone remodeling, though deletion of either gene in bone cells has little impact on the skeletal pattern; and 3) The molecular regulation of cell transformation is highly dependent on the skeletal elements, developmental stage, and different genes. We will test this hypothesis using the following highly related but independent Aims: 1) To determine molecular regulation of cell transformation by Bmpr1a during growth and bone remodeling. Working hypothesis: the CBC defines the overall morphology of the condyle and limbs via BMPR1A that plays variant roles in different elements of the skeleton; and 2): To determine molecular regulation of cell transformation by ?-catenin during growth and bone remodeling. Working hypothesis: ?-catenin plays variant roles in the condyle vs. limbs in defining skeletal pattern and bone remodeling in a manner that differs from Bmpr1a; and 3): To determine how chondrocytes demineralize cartilage matrices and form bone cells ex vivo, and shift expression profiles of genes directly linked to bone cells in vitro. Working hypothesis: HCs, which migrate, play a dual role in removing calcified cartilage and cell transformation. We expect that CBC is responsible for most endochondral bone formation and remodeling, regulated by Bmpr1a and ?-catenin. We predict that this phenomenon also occurs in limbs, although differentially regulated by these genes. Finishing this project will likely revise the current dogma, provide new knowledge in this understudied area, and form a basis for developing novel approaches to prevent, diagnose, and treat TMD, as well as other skeletal diseases.